title: Pivotal role of tissue plasminogen activator in the mechanism of action of electroconvulsive therapy.
abstract: Electroconvulsive therapy is an important treatment option for major depressive disorders, acute mania, mood disorders with psychotic features, and catatonia. Several hypotheses have been proposed as electroconvulsive therapy's mechanism of action. Our hypothesis involves many converging pathways facilitated by increased synthesis and release of tissue-plasminogen activator. Human and animal experiments have shown that tissue-plasminogen activator participates in many mechanisms of action of electroconvulsive therapy or its animal variant, electroconvulsive stimulus, including improved N-methyl-D-aspartate receptor-mediated signaling, activation of both brain-derived neurotrophic factor and vascular endothelial growth factor, increased bioavailability of zinc, purinergic release, and increased mobility of dendritic spines. As a result, tissue-plasminogen activator helps promote neurogenesis in limbic structures, modulates synaptic transmission and plasticity, improves cognitive function, and mediates antidepressant effects. Notably, electroconvulsive therapy seems to influence tissue-plasminogen activator metabolism. For example, electroconvulsive stimulus increases the expression of glutamate decarboxylase 65 isoform in γ-aminobutyric acid-releasing neurons, which enhances the release of tissue-plasminogen activator, and the expression of p11, a protein involved in plasminogen and tissue-plasminogen activator assembling. This paper reviews how electroconvulsive therapy correlates with tissue-plasminogen activator. We suggest that interventions aiming at increasing tissue-plasminogen activator levels or its bioavailability - such as daily aerobic exercises together with a carbohydrate-restricted diet, or normalization of homocysteine levels - be evaluated in controlled studies assessing response and remission duration in patients who undergo electroconvulsive therapy.
authors.affiliation: 1Department of Hematology, Hospital Federal dos Servidores do Estado, Ministry of Health, Rio de Janeiro, Brazil.
authors.forename: Silvia
authors.initials: S
authors.lastname: Hoirisch-Clapauch
authors.forename: Marco A U
authors.initials: MA
authors.lastname: Mezzasalma
authors.forename: Antonio E
authors.initials: AE
authors.lastname: Nardi
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology; D004565:Electroconvulsive Therapy; D006801:Humans; D055495:Neurogenesis; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D010959:Tissue Plasminogen Activator / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology; D015032:Zinc / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D016194:Receptors, N-Methyl-D-Aspartate; D042461:Vascular Endothelial Growth Factor A; D005680:gamma-Aminobutyric Acid; D000255:Adenosine Triphosphate; D010959:Tissue Plasminogen Activator; D015032:Zinc
keywords: Electroconvulsive therapy; N-methyl-D-aspartate; brain-derived neurotrophic factor; major depressive disorders; neurogenesis; purinergic; schizophrenia; tissue plasminogen activator; zinc